![Biological sources of resveratrol. (A) Resveratrol was first isolated from the roots of the white hellebore Veratrum album var. grandiflorum (Veratrum grandiflorum). The phenotype of this plant is characterized by strong and leafy stems arranged in inflorescences (left). The 6 petals of that plant are spread, not adherent, and of white or greenish color (right). (B) The highest concentrations of resveratrol are found in the Japanese knotweed Polygonum japonicum (synonym Fallopia japonica, formerly Polygonum cruspdatum). Originally this herbaceous perennial plant was endemic in East Asia (Japan, China, and Korea) and nowadays can be found in Europe classified as one of the worst invasive plant species. It belongs to the genus Fallopia and its stems hold lots of distinct raised nodes (left). The small white or cream flowers are arranged in erect racemes (right). (C) The content of resveratrol in wines originating from different grape varieties is highly variable. Typically, white wines (e.g., those produced from the varieties White Burgunder, Riesling, Ortega, and Gewürztraminer) contain ;10 times lower resveratrol quantities than wines made from red grapes varieties [such as Cabernet Mitos, Cabernet Cubin, Syrah, Spätburgunder (Pinot noir), Cabernet Sauvignon, and Merlot]. The photos in panels A and B were reproduced from reference 23 with permission. All grape images were taken in Martinsried, Pfalz, Germany. For typical resveratrol concentrations in depicted wines, please refer to Supplemental Table 1.](https://www.researchgate.net/publication/305362627/figure/fig1/AS:560672132038656@1510686061285/Biological-sources-of-resveratrol-A-Resveratrol-was-first-isolated-from-the-roots-of_Q320.jpg)
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REVIEW
Resveratrol: How Much Wine Do You Have to
Drink to Stay Healthy?
1–3
Sabine Weiskirchen and Ralf Weiskirchen*
Institute of Molecular Pathobiochemistry, Experimental Gene Therapy and Clinical Chemistry, Rheinisch-Westfaelische Technische Hochschule
University Hospital Aachen, Aachen, Germany
ABSTRACT
Resveratrol is a naturally occurring stilbene endowed with multiple health-promoting effects. It is produced by certain plants including several
dietary sources such as grapes, apples, raspberries, blueberries, plums, peanuts, and products derived therefrom (e.g., wine). Resveratrol can
be isolated and purified from these biological sources or synthesized in a few steps with an overall high yield. This compound and its glucoside,
the trans-polydatin piceid, have received worldwide attention for their beneficial effects on cardiovascular, inflammatory, neurodegenerative,
metabolic, and age-related diseases. These health-promoting effects are particularly attractive given the prevalence of resveratrol-based
nutraceuticals and the paradoxical epidemiologic observation that wine consumption is inversely correlated to the incidence of coronary
heart disease. However, the notion of resveratrol as a “magic bullet" was recently challenged by clinical trials showing that this polyphenol
does not have a substantial influence on health status and mortality risk. In the present review,wediscusstheproposedtherapeutic
attributes and the mode of molecular actions of resveratrol. We also cover recent pharmacologic efforts to improve the poor bioavailability
of resveratrol and influence the transition between body systems in humans. We conclude with some thoughts about future research
directions that might be meaningful for resolving controversies surrounding resveratrol. Adv Nutr 2016;7:706–18.
Keywords: French paradox, therapy, human trials, liver, SIRT1, pharmacology, nanotechnology
Introduction
Resveratrol is a naturally occurring phytoalexin that is pro-
duced by several plants in response to injury. It exerts multiple
biological activities, including anti-inflammatory, antiprolifera-
tive, and antioxidant effects (1). Structurally, this compound is
astilbenoidthatwasfirst isolated in 1939 from the roots of the
white hellebore (Veratrum grandiflorum) (2) and presumably
received its name from the fact that it is a derivative of the ben-
zene-1,3-diol resorcinol and isolated from the Vera t rum spe-
cies. Subsequently, resveratrol was isolated from several other
plants, fruits, and derivatives, such as grapes, wines, apples,
raspberries, blueberries, pistachios, plums, peanuts, and a mul-
titude of medicinal and edible plant species undergoing response
to stress conditions (3, 4). Experimental and preclinical
studies have attributed several health-promoting effects
to this compound, including cardioprotective effects, che-
mopreventive activity in diverse cancers, and a capacity to
extend the lifespan of lower organisms (5, 6).
The hope and hype concerning resveratrol was initiated by
the finding that phenolic compounds such as the stilbenes ex-
hibit radical scavenger and antioxidant properties (7, 8). This
may account in part for the so-called French paradox originally
formulated in 1981 by French epidemiologists who observed a
lower mortality incidence of coronary heart disease in France
despite high levels of dietary saturated fat and cigarette smok-
ing (9). It was later assumed that moderate drinking of red
wine over a long period of time can protect against coronary
heart disease and might be the cause of this paradoxical
finding (7). Moreover, it was postulated that resveratrol
modulates signaling pathways that limit the spread of can-
cer cells (10), protects nerve cells from damage (11–13),
helps to prevent diabetes (14), and acts as an antiaging agent
that improves age-related problems (15). Rodent models
suggested that this substance might improve consequences
of an unhealthy lifestyle resulting from high caloric intake
(16). In addition, resveratrol has been shown to mediate
therapeutic hepatic effects in acquired and genetic models
of iron overload (17).
1
Supported by Deutsche Forschungsgemeinschaft (DFG) grant SFB/TRR57 P13 and project
E7-6 of the Interdisciplinary Centre for Clinical Research (IZKF) within the Faculty of
Medicine at the Rheinisch-Westfaelische Technische Hochschule Aachen University.
2
Author disclosures: S Weiskirchen and R Weiskirchen, no conflicts of interest.
3
Supplemental Tables 1 and 2 and Supplemental Figures 1 and 2 are available from the
"Online Supporting Material" link in the online posting of the articles and from the same
link in the online table of contents at http://advances.nutrition.org.
*To whom correspondence should be addressed: E-mail: rweiskirchen@ukaachen.de.
706 ã2016 American Society for Nutrition. Adv Nutr 2016;7:706–18; doi:10.3945/an.115.011627.
However, most of the proposed therapeutic cell- and
organ-affecting activities were not confirmed in clinical
trials as of yet, and to our knowledge, there are very few
data regarding the bioavailability of resveratrol in humans.
In healthy subjects, a single dose of resveratrol (100 mg)
combined with polyphenols from a muscadine grape ex-
tract (75 mg) was shown to suppress oxidative and inflam-
matory meal-induced stress response (18). Subjects who
consumed resveratrol (up to 5 g/d) showed decreased cir-
culating levels of insulin-like growth factor-1 (IGF-1)
4
and IGF-binding protein 3 (19). Consistent with the find-
ing obtained in laboratory animals, a meta-analysis showed
that resveratrol improves diabetes (20) and enhances
vascular functions in individuals with mildly elevated
blood pressure (21). On the other hand, the therapeutic ac-
tivity of resveratrol on health status and mortality was crit-
ically questioned by findings showing that the urinary
resveratrol metabolite concentration is not associated with
inflammatory markers, cardiovascular disease, cancer, or
mortality in older community-dwelling adults (22). There-
fore, there is an obvious necessity for more clinical studies
addressing the potential preventive and curative effects of
resveratrol.
In the present review, we highlight the history of resver-
atrol, provide some examples of proposed functions, and
discuss the presumed molecular resveratrol targets. At the
conclusion, we summarize some pharmacologic aspects,
speculate about effective therapeutic drug concentrations,
and supply clues for potential directions of future resveratrol
research.
Current Status
The phenolic compound resveratrol was first isolated in
1939 from the roots of the white hellebore (V. grandiflorum)
(2) (Figure 1A). This perennial, poisonous medicinal plant
is mainly found in China and Japan and contains some
highly toxic steroidal alkaloids. In traditional Chinese med-
icine (TCM), the dried roots and rhizomes of hellebores are
known as “li lu”and are indicated for jaundice, malaria, di-
arrhea, and headache. Resveratrol is also found in other
plants and fruits including grapes, raspberries, blueberries,
plums, and peanuts. The highest concentrations of resvera-
trol are found in the Japanese knotweed Polygonum japoni-
cum (formerly known as Polygonum cruspdatum)(Figure
1B), which is used in TCM in diverse tea products. Origi-
nally this herbaceous plant was endemic in East Asia, Japan,
China, and Korea. Nowadays, the Japanese knotweed is also
found in many countries in Europe and is classified by the
USDA as one of the worst invasive plant species (24). The
high content of resveratrol in this plant has inspired scien-
tists to establish a number of strategies for isolation and pu-
rification of up to 1 g resveratrol from 100 g of extract
acquired from this source (25). In addition, protocols were
developed to biotransform polydatin to resveratrol by firmly
immobilizing edible Aspergillus niger and yeast in roots of
these plants, resulting in 11-fold increased yields (26). The
use of engineered Escherichia coli strains for producing supe-
rior resveratrol titers and advanced chemical synthesis pro-
tocols is another attractive alternative for providing large
quantities of this drug for commercial use (27, 28). In addi-
tion to purified resveratrol, unspecified extracts from these
plants are also available and marketed as dietary health-
promoting supplements. These are generally made from
red wine or grape extracts. Red grape varieties and red wines
contain roughly 3- to 10-fold more resveratrol than their
white counterparts (Figure 1C,Supplemental Table 1).
Resveratrol exists as 2 geometric isomers in which the 2 phe-
nolic rings are either arranged in trans-orcis-configuration
(Supplemental Figure 1).
Although both cis- and trans-isomers of resveratrol occur
in nature, it is generally assumed that the trans-form is bio-
logically more active (29). However, there are also condi-
tions in which the cis-form showed a higher activity (30).
This contradiction may result from the differences in the
chemical stability of both isomers (31) or the occurrence
of transport proteins (e.g., b-lactoglobulin and albumin)
that are viable carriers that stabilize and deliver resveratrol
in vivo in the biologically effective trans-form (32). In addi-
tion, the biological activities of several trans-stilbene deriva-
tives are less potent than their corresponding cis-isomers
(33, 34).
In grapes, both isomers are synthesized almost entirely in
the skin with a peak just before the grapes reach maturity.
The terminal enzyme that is involved in biosynthesis of res-
veratrol is the stilbene synthase, which is activated by exog-
enous stress factors, UV light, and defined chemical signals
from pathogenic fungi (35). Therefore, the content of res-
veratrol and its isomers in the final wine products may
significantly differ between countries, cultivation areas, vin-
tages, and production years (Supplemental Table 1). Despite
this variability, the concentration of cis-resveratrol is generally
proportional to the concentration of its trans-isomer (35).
The average red wine can be expected to contain ;1.9 6
1.7 mg trans-resveratrol/L.
Sources and Recommended Daily Intake of
Resveratrol
It is presumed that major dietary sources of resveratrol in-
clude grapes, wine, apples, peanuts, and soy (4, 36). In Japan
and China, the Itadori tea is another rich source of resvera-
trol. It is made out of knotweed and applied as a traditional
herbal remedy for heart disease and stroke (37). Because the
concentration of resveratrol in all of these food products is
highly variable, it is somewhat difficult to estimate the aver-
age daily intake. According to a study that included 40,685
subjects (aged 35–64 y) from northern and southern regions
of Spain, the estimated median and mean dietary intake
of total resveratrol and its glucoside trans-polydatin piceid
is 100 and 933 mg/d, respectively, and the major sources
in daily life are wines (98.4%) and grapes or grape juices
(1.6%) (38).
4
Abbreviations used: IGF, insulin-like growth factor; SIRT1, sirtuin-1; TCM, traditional Chinese
medicine; tRNA, transfer RNA.
Resveratrol in health and disease 707
This resveratrol intake level might hold true for the Span-
ish population, but resveratrol intake may be completely
different in other countries. As discussed above, exogenous
biological and physical stress factors impact the resveratrol
content in a specific food or beverage. In addition, there
are endogenous factors interfering with the biosynthesis of
resveratrol. In peanut kernels, it was shown that germination
resulted in increased resveratrol biosynthesis, shifting the
concentrations from 2.3–4.5 to 11.7–25.7 mg/g with signifi-
cantly different concentrations in the cotyledons, roots, and
stems (39). Also during the production process of wine, the
resveratrol content is modified by various factors, including
temperature, pH value, and level of SO
2
(35).
The diverse beneficial effects of resveratrol on a specific
disease are strictly dose-dependent, and high doses of resver-
atrol promote unwanted side effects (40). In this context, it
should be mentioned that natural products not only contain
the trans-resveratrol isomers but also the cis-resveratrol iso-
mers. There is a great wealth of other resveratrol dimers and
higher molecular weight resveratrol variants (commonly
classified as “resveratrol oligomers”) occurring in food and
beverages. Most often, these compounds have nonsystematic
names derived from the name of species from which it was
first identified (Supplemental Table 2). For example, Am-
pelopsins, Amurensins, and Hopeaphenol were named after
Ampelopsis brevipedunculata (a wild grape), Vitis amurensis,
and plants of the genus Hopea (e.g., the evergreen tree Hopea
odorata), respectively.
In addition to these oligomers, glycosylated resveratrol
forms occur in nature. It is assumed that the glycosylation
of resveratrol protects this polyphenol from enzymatic oxida-
tion, thereby extending the cellular half-life and preserving
the antioxidant capacity (41). All of these factors make it dif-
ficult to accurately estimate the exact daily uptake of resvera-
trol in food products. Therefore, a number of manufacturers
sell pharmaceutically produced supplements with the resver-
atrol content exactly specified. Most often, these “highly
potent”drugs are offered with “more is better”recom-
mendations, and some of these “health bomb”formulations
are offered with obscure and unscientific instructions sug-
gesting doses of 1 g resveratrol to achieve the best health im-
provement effects. The recommended amount is equivalent
to a dosage of 12.5 mg/kg body weight if an adult of 80 kg
is assumed. These concentrations are justified by rough
FIGURE 1 Biological sources of resveratrol. (A) Resveratrol was first isolated from the roots of the white hellebore Veratrum album var.
grandiflorum (Veratrum grandiflorum). The phenotype of this plant is characterized by strong and leafy stems arranged in inflorescences
(left). The 6 petals of that plant are spread, not adherent, and of white or greenish color (right). (B) The highest concentrations of
resveratrol are found in the Japanese knotweed Polygonum japonicum (synonym Fallopia japonica, formerly Polygonum cruspdatum).
Originally this herbaceous perennial plant was endemic in East Asia (Japan, China, and Korea) and nowadays can be found in Europe
classified as one of the worst invasive plant species. It belongs to the genus Fallopia and its stems hold lots of distinct raised nodes
(left). The small white or cream flowers are arranged in erect racemes (right). (C) The content of resveratrol in wines originating from
different grape varieties is highly variable. Typically, white wines (e.g., those produced from the varieties White Burgunder, Riesling,
Ortega, and Gewürztraminer) contain ;10 times lower resveratrol quantities than wines made from red grapes varieties [such as
Cabernet Mitos, Cabernet Cubin, Syrah, Spätburgunder (Pinot noir), Cabernet Sauvignon, and Merlot]. The photos in panels A and B
were reproduced from reference 23 with permission. All grape images were taken in Martinsried, Pfalz, Germany. For typical resveratrol
concentrations in depicted wines, please refer to Supplemental Table 1.
708 Weiskirchen and Weiskirchen
extrapolations from animal experiments, most of which re-
quire daily dosages of 5–100 mg resveratrol/kg body weight
in order to reach a specific biological effect.
Clinical trials assessing the effects of resveratrol in humans
are rather rare, and some were performed by using grape ex-
tracts without precise knowledge of resveratrol concentra-
tions, making it difficult to interpret the results. In one
study, resveratrol was administered to healthy volunteers
(n= 10) at 1 of 4 daily dosages (0.5, 1.0, 2.5, or 5 g) over
the course of 29 d. There was a substantial decrease in circu-
lating IGF-1 and IGF-binding protein 3 among volunteers re-
ceiving 2.5 g/d compared with predosing values. In this study,
it was further shown that the daily uptake of 2.5 and 5 g
caused mild to moderate gastrointestinal symptoms (19). An-
other clinical study in which 42 healthy volunteers consumed
1 g resveratrol/d for 4 wk showed that this regimen was suf-
ficient to modulate enzyme systems that are involved in car-
cinogen activation and detoxification pathways (42). Even
lower doses (5 mg 2 times/d for 4 wk) of a novel resveratrol
formulation termed SRT501 were effective inimproving insu-
lin sensitivity in patients with type 2 diabetes, although
SRT501 was originally developed for treatment of multiple
myeloma (43). Similarly, a previous study suggested that
higher doses of 2.5 and 5 g resveratrol/d for 28 d were thera-
peutically effective in patients with type 2 diabetes (44). Al-
though the last 2 studies (42, 43) are highly encouraging,
the observation that different daily doses (10 mg compared
with 5 g) applied in human studies are equally effective indi-
cates a scientific dilemma and further raises the question
about the necessary amount that should be applied to cure
a specific disease. Moreover, the fact that the development of
the resveratrol drug SRT501 was halted because of side effects
(nausea, vomiting, and diarrhea) raised controversial ques-
tions about the overall therapeutic applicability of resveratrol,
resveratrol-enriched supplements, and resveratrol formulations.
Nevertheless, safety studies in humans have shown that res-
veratrol is a safe drug and is reasonably well tolerated at doses
of up to 5 g/d (19, 45). Therefore, the overall low toxicity of
resveratrol should in principle allow the translation of the en-
couraging experimental findings to humans. In contrast
to this assumption, the overall conclusion of a detailed litera-
ture analysis (46) highlighting resveratrol benefits and side ef-
fects, proposed resveratrol activities, and issues of relevant
resveratrol dose for treatment of human diseases was that
the published evidence is not sufficiently strong to justify
a recommendation for the administration of resveratrol to hu-
mans. In addition, the study indicated that an optimal dose of
resveratrol has yet to be established in human studies (46).
However, numerous reports describe therapeutic and health-
promoting benefits of resveratrol consumption, and these
benefits affect many organs (Figure 2). However, most of
these therapeutic activities were only established in cell culture
or in preclinical models. We discuss some of the most impor-
tant findings of health-promoting effects in the following
paragraphs.
Beneficial Effects of Resveratrol
Beneficial effects of resveratrol in heart disease
There are a number of reports describing the beneficial ef-
fects of resveratrol on improvement of heart dysfunction,
FIGURE 2 Some of the reported beneficial effects of resveratrol on organ function.
Resveratrol in health and disease 709
failure, calcification, and pressure overload, as well as the
attenuation of myocardial hypertrophy by virtue of its an-
tioxidant, antihypertensive, and coronary vasodilating activ-
ities (47). At the molecular level, most likely some of these
effects are mediated through activation of silent information
regulator 1 (SIRT1; also known as Sirtuin 1), 59-adenosine
monophosphate-activated protein kinase, and endogenous
antioxidant enzymes (48). A recent study of the pathogene-
sis of myocardial fibrosis suggested that resveratrol exhibited
its therapeutic effects by inhibiting pathways that were
driven by reactive oxygen species, extracellular regulated
kinases, TGF-b, and periostin (49). In addition, resvera-
trol was shown to prevent collagen expression in cardiac
fibroblasts and to protect against drug-induced cardiotox-
icity (50, 51). The therapeutic effects of resveratrol in
these models could be attributed to the capacity of resver-
atrol to protect against drug-induced glutathione deple-
tion and superoxide dismutase activity (51). A recent
meta-analysis of 6 randomized controlled trials compris-
ing a total of 247 subjects showed that high levels of resver-
atrol consumption significantly decreased the systemic
blood level, although it had no effect on diastolic blood
levels (52).
Beneficial effects of resveratrol in breast cancer
The impact of resveratrol on breast cancer is controversial.
Although some reports showed that resveratrol supplemen-
tation prevented experimental mammary carcinogenesis
(53, 54), other studies found that low concentrations of res-
veratrol promoted breast cancer (55). Resveratrol decreased
breast cancer cell proliferation in a dose-dependent manner
(56). Novel aza-resveratrol analogues have already been
tested for their potential to inhibit the proliferation of breast
cancer cells by impacting the expression of estrogen recep-
tors (57). In a pilot study conducted in 40 postmenopausal
women with high BMI, a resveratrol intervention with 1 g
resveratrol/d for 12 wk had favorable effects on estrogen me-
tabolisms and increased the concentrations of the sex steroid
hormone-binding globulin, which is inversely associated to
breast cancer risk (58). Likewise, a randomized double-blind
study of 39 adult women with increased breast cancer risk
showed decreased methylation of the tumor suppressor
gene RASSF-1a(Ras association domain family member
1-a) in resveratrol-treated patients compared with non-
treated subjects and suppression of expression of the cancer
promoting PGE
2
(59). However, this study was conducted
with a limited sample size and needs to be validated in larger
cohorts.
Beneficial effects of resveratrol on bone homeostasis
Favorable effects of resveratrol on bone homeostasis have
also been reported. In one study, it induced osteogenesis,
prevented osteoarthritis, and counteracted age-related bone
loss (60). Likewise, the oral administration of resveratrol sig-
nificantly prevented bone loss and osteoclastogenesis in
a murine iron overload-induced bone loss model (61). In
this model, the application of resveratrol reverted the
iron-induced reduction of the bone transcription factor
Runx2, the bone-building Osteocalcin, and type I collagen.
These data suggest that resveratrol mediates bone building
by stimulation of osteoblastic and inhibition of osteoclastic
activities. In line with this assumption, a randomized, placebo-
controlled trial that enrolled 74 middle-aged obese men
showed that oral treatment with 1 g resveratrol/d for 16 wk
promoted formation and mineralization of bone (62).
Resveratrol effects on the pancreas and glucose
metabolism
Oral gavages of resveratrol in methylglyoxal-treated mice in-
creased pancreatic cellular insulin content, suggesting that
this polyphenol may be useful in the treatment of type 2 di-
abetes by protecting against pancreatic cell dysfunction (63).
In humans, there are reports that have shown that resvera-
trol improves glucose homeostasis, decreases insulin resis-
tance, and decreases metabolic disorders, suggesting that
resveratrol has the potential to treat diabetes (64). Based
on experimental findings that were established in rats that
were maintained on a high-fat diet, it is most likely that
some of the therapeutic effects of resveratrol on energy ho-
meostasis and glycemic control were induced by the antiox-
idant function of resveratrol and its capacity to modulate
mitochondrial activities and restore insulin secretion dys-
function (65).
Renal effects of resveratrol
With regard to the kidney, independent reports have shown
that resveratrol attenuates renal injury, fibrosis, unwanted
drug toxicity, and oxidative and diabetes-associated damage
(66–68). Recently, it was demonstrated that resveratrol po-
tentiates vitamin D and nuclear receptor signaling, possibly
elucidating a possible molecular pathway of resveratrol ac-
tivity (69). An inhibitory effect of resveratrol on epithelial-
mesenchymal transition, a process that is associated with
the progression of fibrosis, was recently demonstrated in
the human tubular epithelial cell line HK-2 (66). In the study,
it was demonstrated that resveratrol increased expression of
SIRT1 and inhibited TGF-bpathway via deacetylation of
Smad4, the common intracellular mediator of TGF-b
signaling (66).
Resveratrol and the visual system
Similar positive effects were reported in the eye; resveratrol
protected lens and corneal epithelium, as well as retinal pho-
toreceptor cells, from diabetic complications and other
kinds of damage (70, 71). Comparable to the observations
that were found in renal cells, epithelial-mesenchymal tran-
sition was significantly inhibited in retinal pigment epithelial
cells, suggesting that resveratrol is a potential drug suitable
for the treatment of proliferative vitreoretinopathy, a disease
marked by retinal detachment and ocular trauma (72). In
this model system, resveratrol also leads to a substantial de-
acetylation of Smad4, which resulted in reduced fibrotic
membrane formation. In a diabetic cataract rat model,
a protective effect of resveratrol on lensepithelial cell apoptosis
710 Weiskirchen and Weiskirchen
was demonstrated by reduced expression of caspase-3 and
lower apoptotic ratios (73).
Resveratrol and fertility
With regard to the ovaries, resveratrol was shown to be an ef-
fective therapy for conditions associated with androgen
excess, thereby protecting against age-dependent decline in
fertility by increasing the ovarian follicular reserve, ovarian
life span, and preventing oocyte apoptosis (74). Other reports
have shown that resveratrol restores erectile function in ex-
perimental models of rats with diabetes, a finding that
was mainly reflected by improvement of intracavernous pres-
sure, mean arterial blood pressure, and modulation of cavern-
ous cyclic GMP levels (75). Recently, it was shown that
resveratrol supplementation modulates oxidative stress, JNK
signaling, and caspase-3 activities, thereby counteracting
diabetes-induced decreases in reproductive organ weights,
sperm count, and motility (76). Similar effects on sperma-
togenesis and general testicular germ cell differentiation of
resveratrol were also reported in surgically rendered cryp-
torchid mice (77).
Resveratrol and the blood system
Resveratrol has been shown to affect platelet aggregation and
apoptosis, most likely by increasing ATP, ADP, and AMP hy-
drolysis (78). It was recently demonstrated that this activity
by resveratrol is useful in preventing unwanted activation of
human platelets during storage for transfusion purposes (79).
The study showed that human platelets treated with resveratrol
released less thromboxane B
2
and PGE
2
than did control plate-
lets, showed decreased platelet apoptosis in storage, and had a
longer half-life following transfusion (79). Furthermore, it
could be demonstrated that resveratrol decreases the secretion
of PGE
2
, CCL5/RANTES, and CXCL8/IL-8 and increases
production of IL-1b, IL-6, and IL-10 in LPS-stimulated
peripheral blood leukocytes (80). Independent in vitro exper-
iments that were performed in polymorphonuclear leuko-
cytes isolated from healthy, adult dogs also demonstrated
that resveratrol increased proinflammatory and decreased
anti-inflammatory leukocyte cytokine production in leu-
kocytes (81). These data also show that resveratrol is effec-
tive in reducing the robustness of oxidative burst capability
in leukocytes (81).
Pulmonary effects of resveratrol
In the lungs, resveratrol has been shown to be effective in pre-
venting dysfunction, fibrogenesis, cancer growth, and injury-
induced cell apoptosis and further in displaying antiasthmatic
effects and modulating the activity of drug-metabolizing en-
zymes (82, 83). Novel studies that investigated the effects of res-
veratrol on hypoxia/reoxygenation-induced alveolar epithelial
cell dysfunction suggested that the therapeutic effects of res-
veratrol are partially mediated by promoting surfactant pro-
tein expression and inhibiting the NF-kB signaling pathway,
which controls many genes involved in inflammation (84).
Also some resveratrol oligomers such as cis-andtrans-gnetin
H, which are widelyapplied in TCM, were tested in vitro; were
capable of promoting apoptosis by releasing mitochondria cy-
tochrome c, activating caspase 3 and 7, and inhibiting NF-kB
activation in 4 human cancer cell lines; and were therapeuti-
cally efficient in suppressing the growth of xenograft lung tu-
mors in mice (85).
Neuroprotective effects of resveratrol
Several neuroprotective effects of resveratrol have been re-
ported, including protection against neuronal damage and
ammonia toxicity, abrogation of depression, improvement
of cognitive dysfunction, and increased ability in spatial
learning and memory (86, 87). In a model of rats with mid-
dle cerebral artery occlusion, resveratrol reduced ischemia-
induced apoptosis in the hippocampus in a dose-dependent
manner, indicating that resveratrol is a neuroprotective sub-
stance with therapeutic potential (88). In line with these find-
ings, a recent report in which resveratrol’s neuroprotective
effects were evaluated in neonatal rats showed that resveratrol
effects are long lasting, protecting against brain damage,
reducing infarct volume, and ameliorating the loss of my-
elination (89).
Hepatic effects of resveratrol
Other studies have investigated the therapeutic potential of
resveratrol in hepatic disease models. Experimentally, there
are clear indications that resveratrol ameliorates hepatic lipid
accumulation and progression of nonalcoholic steatohepatitis
by downregulation of inflammatory signaling pathways
and regulation of autophagy (90). In the underlying study,
the authors fed mice a methionine-choline deficient diet and
found that the daily intragastric administration of resveratrol
(100 or 250 mg/kg body weight) attenuated hepatic steatosis
and inflammation. In contrast, resveratrol treatment had no
consistent therapeutic effects on the alleviation of mani-
fest experimental steatohepatitis (91). Although these findings
may suggest that resveratrol treatment has preventive but
not curative activities in the pathogenesis of liver diseases,
daily supplementation with 500 mg resveratrol for 12 wk
improved the outcomes in a randomized, double-blinded,
controlled clinical trial that enrolled 50 patients with nonal-
coholic fatty liver disease (92).
The resveratrol tetramer vitisin B is a highly potent in vitro
inhibitor of the hepatitis C virus helicase (93). Furthermore,
in mice that received injections of cancer cells, resveratrol sig-
nificantly inhibited hepatic retention and metastatic growth of
melanoma cells, most likely by interfering with IL-18 secre-
tion, suppressing VCAM-1 expression, and blocking the stim-
ulatory effects of IL-18 on cell adhesion and proliferation (94).
Most recently, it was shown that resveratrol protects the liver
from iron-mediated injury, which is causative in the forma-
tion of acquired and genetic iron-overload diseases (17).
The therapeutic potential of resveratrol was also successfully
proven in models of colorectal and prostate cancer (95, 96).
Resveratrol and muscle
Several independent reports have found favorable effects of
resveratrol on muscle function and injury. In experiments in
Resveratrol in health and disease 711
which the tibialis region of the hind limbs of rats was sub-
jected to compression injury by 2 cycles of 6-h constant
pressure, administration of resveratrol at daily concentra-
tions of 25 mg/kg prevented the compression-induced man-
ifestations of pathohistologic damages and ameliorated
oxidative damages in a SIRT1-dependent manner (97). Sim-
ilarly, the combined dietary intake of 500 mg resveratrol and
10 mg piperine for 4 wk was recently shown to increase
skeletal muscle mitochondrial capacity upon low-intensity
exercise training (98). Interestingly, resveratrol drastically
impacted the muscle fiber characteristics and antioxidative
capacity of finished pigs, suggesting that resveratrol is an
effective additive to improve pork meat quality (99). Like-
wise, juvenile Southern flounders that were fed a diet sup-
plemented with 600 mg resveratrol/g of food for 16 wk
showed a greater length and body mass than fish fed a con-
trol diet (100). Such studies indicate that resveratrol is a
new supplement to enhance growth in different agricul-
tural and aquacultural settings.
Molecular Activities of Resveratrol
Potential molecular functions of resveratrol were first
reported in 2003 (5). In this pioneering work, it was shown
that resveratrol can modulate the activity of SIRT1, a critical
deacetylase that impacts the acetylation status of p53, fork-
head proteins, and DNA repair enzymes (5). On the other
hand, activation of SIRT1 by resveratrol treatment reduced
tumorigenesis in a mouse model (101). As a consequence,
the binding of resveratrol to SIRT1 is associated with a sig-
nal that mimics calorie restriction and increases DNA
stability, resulting in extended lifespan of Saccharomyces cer-
evisiae (5). Valuable insights on the structural basis of the
resveratrol-SIRT1 interaction and its potential molecular
details on SIRT1 activity regulation by resveratrol were re-
cently obtained from crystal structure analysis (Supplemen-
tal Figure 2) (102). The study suggests that the binding of
different resveratrol molecules to the N-terminal domain
of SIRT1 is principally responsible for promoting tighter
binding between SIRT and a 4-residue acetylated p53 peptide
(i.e., 7-amino-4-methylcoumarin), thereby increasing SIRT1
activities.
Other recent findings considered the possibility that the
tyrosine-like phenolic ring of resveratrol might fit into the
active site pocket of tyrosyl transfer RNA (tRNA) synthe-
tase, which affects downstream activation of key stress
signaling pathways (103). In addition, the binding of resver-
atrol to tyrosyl tRNA synthetase nullifies catalytic activity of
this enzyme and redirects the tRNA synthetase to a nuclear
function, stimulating NAD
+
-dependent auto-poly-ADP-
ribosylation of poly(ADP-ribose) polymerase 1 (103). Resver-
atrol was also shown to bind to the F1-ATPase from heart
mitochondria, thereby probably preventing its proper func-
tionality in mitochondrial ATP synthesis (104). Such an
activity would explain resveratrol activity on cellular prolif-
eration and apoptosis.
In another study, the authors used a structure-based drug
discovery strategy that relies on metabolomics-biased
fragment crystallography in which a library is screened
against leukotriene A4 hydrolase, an enzyme that is closely
linked to a rachi donic acid metabo lism. Using this screen-
ing method, the authors identified resveratrol as an efficient
ligand for leukotriene A4 hydrolase (105). This finding
might explain the antioxidant activity of resveratrol and fur-
ther provide some clues about the molecular details of
how resveratrol modulates inflammatory responses. Well-
designed binding studies using fluorescence spectroscopy
and surface plasmon resonance techniques showed that res-
veratrol also has affinity for phospholipase A
2
, another key
factor that plays a role in arachidonic acid metabolism and
catalyzes the hydrolysis of phospholipids into arachidonic
acid and lysophospholipids (106). This in turn provides
another good explanation of how resveratrol interferes
with inflammatory signaling. Along those lines, crystallo-
graphic analysis and functional studies showed that resvera-
trol acts as a pathway-selective estrogen receptor-aligand,
again offering another pathway by which resveratrol modu-
lates the inflammatory response (107).
During recent years, intensive studies have focused on
gaining a better molecular understanding of the proposed
insulin-sensitizing function of resveratrol. X-ray crystallo-
graphic studies and in vitro transactivation assays showed
that resveratrol acts as a PPAR antagonist through its direct
interaction with PPARgand PPARa(108). Other investiga-
tions that analyzed crystal protein-resveratrol complexes
found an affinity for resveratrol and other polyphenols for
insoluble transthyretin, which is relevant in the pathogenesis
of diverse amyloid disorders such as familial amyloid poly-
neuropathy, familial amyloid cardiomyopathy, and senile
systemic amyloidosis (109). The precise molecular and
structural basis of this interaction was recently determined
in high resolution (110). These insights may provide the
molecular basis to understand some of the reported benefi-
cial neuro- or cardioprotective effects of resveratrol that are
due to increased fibrillogenesis and enable potential new
therapeutic intervention strategies for targeting unwanted
transthyretin aggregations within a specific tissue.
Biotransformation and Pharmacologic Aspects
in Resveratrol Biology
As outlined above, there is a wealth of literature describing
beneficial effects of resveratrol in diverse preclinical disease
models. However, the clinical potential of resveratrol is some-
what difficult to estimate because there is insufficient infor-
mation about optimal dosage, biotransformation, potential
side effects, and pharmacokinetic parameters. In addition,
there are a number of parameters and pharmacologic consid-
erations that affect the rate of active and passive individual
absorption in the gastrointestinal tract (111). Unfortunately,
most of the studies that investigated pharmacologic aspects
of resveratrol were done only in healthy volunteers, and there
is no guarantee that these findings can be recapitulated in dis-
eased patients. In addition, compared with its solubility in
ethanol (;50 g/L), the aqueous solubility of resveratrol
(;3 mg/100 mL) is rather low, suggesting that alcoholic
712 Weiskirchen and Weiskirchen
beverages are beneficial to increase resveratrol’s bioavailability
and peak plasma concentrations. Likewise, the administration
of special galenic formulations of resveratrol is potentially
suitable to increase the bioavailability of resveratrol. For ex-
ample, in patients with colorectal cancer with hepatic metas-
tases scheduled to undergo hepatectomy, the application of
the micronized resveratrol formulation SRT501 induced
3.6-fold higher plasma levels than those published for equiv-
alent doses of nonmicronized resveratrol. This drug formu-
lation further extended the mean half-life by over 1 h and
almost doubled the time to maximum plasma concentra-
tions (112). Other approaches to increase the bioavailability
of resveratrol arose from the finding that the combined appli-
cation of resveratrol with other molecules such as pterostil-
bene, a stilbenoid chemically related to resveratrol, can
result in synergistic and additive effects in breast cancer cell
lines (113). Likewise, the combination of resveratrol and v-3
PUFAs exerted synergistic effects on CCL5/RANTES expres-
sion in LPS-stimulated human peripheral blood leukocytes
and additive effects on IL-6 or CXCL8/IL-8 expression in
IL-1b-activated chondrocytes (80). Similarly, the synthesis of
higher molecular oligomers of resveratrol and analogues is
currently studied as an option to increase the selectivity of res-
veratrol activity. Compared with resveratrol, the triple-bond
resveratrol analogue (i.e., 3,4’,5-trihydroxy-diphenylacetylene)
had weaker antioxidant activity and stronger inhibitory effect
on NF-kB activation and on cyclooxygenase-2, TNF-a,and
IL-6 production in the mouse leukemic monocyte macrophage
cell line RAW 264.7 (114).
On the other hand, methylated resveratrol was shown to
increase antitumor activity but failed to mediate beneficial
metabolic effects in vitro and mediated its cell growth inhib-
itory effects at different stages (115). These findings suggest
that structural optimization approaches targeting the resver-
atrol molecule might be suitable to selectively change its ac-
tivity into a desired direction.
Resveratrol Prodrugs
As discussed above, the therapeutic usage of resveratrol is
somewhat hampered by its low bioavailability. As a com-
pound that is poorly soluble in water, resveratrol is effec-
tively absorbed by passive diffusion in the intestine where
it is then transported into the liver. Before it reaches the
systemic circulation, the presystemic metabolism (i.e., first
pass effect) in the liver leads to a substantial reduction of
free resveratrol (116). Resveratrol is conjugated in phase II
metabolism to higher soluble glucuronides (e.g., resveratrol-
3-O-glucuronide, resveratrol-4-O-glucuronide) and sulfates
(e.g., resveratrol-trisulfate) or is bound to albumin and lipo-
proteins (116). Thus, the therapeutic efficacy of resveratrol
after oral administration is rather low. Therefore, efforts
that either increase the bioavailability of resveratrol or delay
its phase II metabolism by delivering resveratrol as a pro-
drug are primary targets for the biomedical exploitation of
resveratrol (117). Recently, it was demonstrated that the en-
gagement of the free OH groups within resveratrol into an
N-monosubstituted carbamate linkage with natural amino
acids prevents conjugation, increases the stability at low
pH values, and decreases the rate of hydrolysis (117). An-
other strategy that is based on polymer conjugation by using
ester- and ether-based polyethylene glycol and polyethylene
glycol-polylactide linker chemistry allowed researchers to
increase the half-life of resveratrol in rat plasma from 0.13
to 3 h (118). There are also intensive efforts to develop strat-
egies to prepare liposome- or nanotechnology-based resver-
atrol formulations for enhancing the aqueous solubility and
stability or improving the rate and extent of absorption
(119, 120). In addition, resveratrol is used as a blueprint
for the design and synthesis of novel, more potent drugs.
HS-1793, for example, is a resveratrol analogue that is free
from the restriction of metabolic instability, bypassing the
high-dose requirement in therapeutic use. This substance
was shown to induce cell cycle arrest and apoptotic cell
death in breast cancer cell lines more effectively than resver-
atrol and maintain its good compatibility in standard tests of
genotoxicity (121, 122). Some innovative soluble galenic
forms of resveratrol should, in principle, also improve the
bioavailability and efficiency of resveratrol in humans,
thereby allowing a decreasing drug burden in humans (123).
Therapeutic Doses of Resveratrol and the
French Paradox
Current recommendations for daily consumption of resvera-
trol are primarily based on arithmetical animal-to-human
dosage conversion. Unfortunately, the confirmation of thera-
peutic effectiveness of these calculated resveratrol concentra-
tions in humans is still pending (124). Independent studies
have shown that resveratrol consumption in a daily range
of 700–1000 mg/kg body weight is well tolerated without tox-
icologic effects and that concentrations #2 g/d are harmless
when applied in the short term (46, 125). Based on these
and other findings, various “experts”claim that a daily dosage
of 1 g/d is effective for treatment of diverse disorders in hu-
mans. In addition, the permanent launch of articles with a
lack of scientific background has led to the notion that the
consumption of supplements enriched with resveratrol is
health-promoting or suitable to alleviate diverse medical con-
ditions. Moreover, the uncritical acceptance and erroneous
interpretation of the French paradox, which links a lower
incidence of coronary heart disease with the chronic con-
sumption of low doses of red wine or intake of other resver-
atrol-containing nutrients, have led to the assumption that
red wine, grapes, peanuts, chocolate, Itadori tea, or other
foods or beverages are a kind of “daily health therapy.”
However, one wonders how much of these nutrients
must be consumed to reach the RDA of 1 g resveratrol. Typ-
ical resveratrol concentrations reported for conventional
food products are: peanuts without seed coats, 0.03–
0.14 mg/g (126); red wines, 0.361–1.972 mg/L (127); white
wines, 0–1.089 mg/L (128); rosé wines, 0.29 mg/L (129);
beers, 1.34–77.0 mg/L (130); skin of tomatoes, ;19 mg/g
dry weight (131); dark chocolate, 350 mg/kg; milk chocolate,
100 mg/kg (132); Itadori tea, 68 mg/100 mL (37); red
grapes, 92–1604 mg/kg fresh weight (133); white grapes,
Resveratrol in health and disease 713
59–1759 mg/kg fresh weight (133); and apples, 400 mg/kg
fresh weight (4). On the basis of these given concentrations,
it is not possible to absorb the recommended dose of re-
sveratrol through uptake of any of these nutrients or com-
binations thereof (Figure 3). This inevitably raises the
question: how can scientists justify the French paradox by
drinking red wine or consuming other foods or beverages?
The newest annual report on wine published by the Global
Agricultural Information Network reveals that France is the
world’s biggest wine producer (4.6 billion liters in 2014)
and consumer with a per capita consumption of 43.4 L in
2014 (134). Assuming ;73% of these wines are red/rosé
wines and 27% are white wines, and further adopting that
red/rosé wines contain ;2 mg/L resveratrol and white wines
contain ;0.5 mg resveratrol/L, the annual consumption of
31.7 L of red wine and 11.7 L of white wine is equal to an up-
take of ;70 mg resveratrol/y (or 0.2 mg/d) or 5000 times less
than the proposed therapeutic dose of 1 g/d. Even if further
daily resveratrol sources (grapes or peanuts) are considered,
these rough calculations clearly document that the consump-
tion of red wine is not a good explanation of the pathologic
mechanisms predicting the French paradox.
Of course, we must admit that our calculations only con-
sider the amount of unbound resveratrol in respective
beverages and foods. As discussed above, many of the men-
tioned nutrients contain higher molecular constituents (i.e.,
resveratrol oligomers) and resveratrol glucosides (e.g., trans-
polydatin piceid), which often occur in high concentra-
tions and show similar or sometimes higher potency in
cell culture and animal studies (135, 136). Unfortunately,
the knowledge of these oligomeric entities is poor, and the
pharmacologic properties of these compounds are widely
unknown. In this regard, the continuous development of da-
tabases, such as the Phenol-Explorer, that provide informa-
tion about the polyphenol content in foods, would be
extremely helpful in estimating the daily uptake of resvera-
trol and resveratrol derivatives (137, 138). In addition, in-
vestigation of long-term resveratrol consumption safety,
especially in medicated individuals, is urgently needed to es-
timate the therapeutic potential of resveratrol for clinical sig-
nificance in the daily care of patients (139).
Another critical issue isthe targeting of resveratrol activities
to a specific organ. In most of the preclinical studies per-
formed in animals, resveratrol was orally or intraperitoneally
administered, resulting in a systemic distribution. Currently,
there are several investigations aiming to develop nanotech-
nology-based formulation, i.e., resveratrol-encapsulated nano-
particles, to improve pharmacokinetic properties and to
enhance targetability and bioavailability of resveratrol (140).
In summary, it is certainly valid to argue that it is not pos-
sible to take up 1 g of unbound resveratrol/d by consuming
conventional food products. Alternatives that are offered by
many companies include a variety of (sometimes outrageously
expensive) nutritional supplements with precisely defined re-
sveratrol content. Although their clinical usefulness is ques-
tionable, they are advertised with extravagant promises. It
will be interesting to see how new experimental findings in re-
sveratrol research will be translated into the clinics.
FIGURE 3 Quantities of food
and beverages that must be
consumed to reach
therapeutic doses. Based on
animal studies, daily
resveratrol doses in the range
of hundreds of milligrams to
several grams for therapeutic
intervention have been
proposed. If a person intends
to ingest 1 g resveratrol each
day, this would require
consuming the depicted
quantities of foods or
beverages. The calculation is
based on typical resveratrol
contents found in peanuts
without seed coats (0.03–0.14
mg/g) (126), red wine (Pinot
noir from France, 0.362–1.979
mg/L) (127), white wine
(Riesling from Spain, 0.057–
0.390 mg/L) (128), rosé wine
from Serbia (0.29 mg/L) (129),
beer (1.34–77.0 mg/L) (130), skin of tomato (;19 mg/g dry weight) (131), dark chocolate (350 mg/kg), milk chocolate (100 mg/kg) (132),
Itadori tea (68 mg/100 mL, when prepared by infusing 1 g of the commercial root prepared with 100 mL of boiling water for 5 min) (37),
red Merlot grapes from Japan (1259 mg/kg fresh weight) (133), white Riesling grapes from Japan (387 mg/kg fresh weight) (133), and
cultivated apples (estimating a mean total content of 400 mg/kg fresh weight found in 150 different cultivars) (4).
714 Weiskirchen and Weiskirchen
Conclusions
Resveratrol is a polyphenol that is present in the human diet
and has a large variety of potential therapeutic properties.
However, it is not possible to absorb the recommended ther-
apeutic doses of resveratrol by drinking wine or through die-
tary sources. In addition, to date, most ofthe beneficial effects
are only established in preclinical models. One of the major
challenges in resveratrol research is to determine whether
the observed health-promoting effects are transferable to hu-
mans.Therefore,clinicaltrialswiththeaimofdetermining
the effective dosage regimen for the therapy of specificdiseases
are urgently needed. These trials must be conducted with well-
standardized resveratrol formulations in order to allow the
comparison of obtained results. Because previous studies in
humans have already consistently shown that the bioavailabil-
ity of resveratrol after oral intake is rather low, the development
of resveratrol formulations with better pharmacologic proper-
ties is still a challenging task. Likewise, structural optimization
and the development of new galenic resveratrol formulations
such as resveratrol-encapsulated nanoparticles should help
to physiologically increase resveratrol’s activity and overall bio-
availability, to lower the necessary dose, to prevent unwanted
side effects during therapy, and to target resveratrol activities
to specific organs. Resveratrol-enriched supplements might
be suitable to allow daily uptake of therapeutically relevant
doses (currently presumed to be 1 g) that are not obtainable
by conventional foods or beverages. In addition, resveratrol
might be a supplement that enhances growth or quality of
products cultured in different agricultural and aquacultural
settings, thereby developing health-promoting effects. In
this regard, the intensification of research of resveratrol oligo-
mer chemistry and biology may also offer some avenues for
new therapeutic drugs with better pharmacologic properties.
In the long term, such investigations will reveal whether all
the hype and hope associated with resveratrol are scientifically
justified.
Acknowledgments
The authors thank Hiroshi Moriyama (23) for providing
images for this review and Kevin Brulois for critical reading
of the manuscript. All chemical structures depicted were
generated with the open source molecule viewer Jmol (ver-
sion 14.2.15_2015.07.09) that is freely available (141). Drawn
pictures were prepared with CorelDRAW X6 (Corel GmbH,
Munich, Germany). SW provided photographs and prepared
the final figures for this review. RW drafted the text and pro-
vided ideas for images. Both authors read and approved the
final manuscript.
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